This invention relates generally to novel spiro-cyclic xcex2-amino acid derivatives as matrix metalloproteinases (MMP), TNF-xcex1 converting enzyme (TACE), and/or aggrecanase inhibitors, pharmaceutical compositions containing the same, and methods of using the same.
There is now a body of evidence that metalloproteases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMPs (tissue inhibitors of metalloprotease), which form inactive complexes with the MP""s.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 1970, 52A, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteases. The available evidence supports that it is the metalloproteases that are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 1978, 21, 761-766, Woessner et al. Arthritis Rheum. 1983, 26, 63-68 and Woessner et al. Arthritis Rheum. 1984, 27, 305-312). In addition, aggrecanase has been identified as providing the specific cleavage product of proteoglycan found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 1993, 36, 1214-22).
Therefore, metalloproteases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 1990, 25, 175-184, AP, San Diego).
Tumor necrosis factor-xcex1 (TNF-xcex1) is a cell-associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF-xcex1 has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF-xcex1 has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF-xcex1 with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al. Lancet 1994, 344, 1105), non-insulin dependent diabetes melitus (Lohmander, L. S. et al. Arthritis Rheum. 1993, 36, 1214-22) and Crohn""s disease (MacDonald et al. Clin. Exp. Immunol. 1990, 81, 301).
Compounds which inhibit the production of TNF-xcex1 are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently, TNF-xcex1 converting enzyme (TACE), the enzyme responsible for TNF-xcex1 release from cells, were purified and sequenced (Black et al. Nature 1997, 385, 729; Moss et al. Nature 1997, 385, 733). This invention describes molecules that inhibit this enzyme and hence the secretion of active TNF-xcex1 from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, OA, RA, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF-xcex1 production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF-xcex1 production may also have a particular advantage in diseases where both mechanisms are involved.
EP 0,780,286 describes MMP inhibitors of formula A: 
wherein Y can be NHOH, R1 and R2 can combine to form a cycloalkyl or heterocyclo alkyl group, R3 and R4 can be a variety of groups including H, and R5 can be substituted aryl.
WO 97/20824 depicts MMP inhibitors of formula B: 
wherein ring V contains six atoms, Z is O or S, and Ar is an aryl or heteroaryl group. Ar is preferably a monocyclic aryl group with an optional para substituent or an unsubstituted monocyclic heteroaryl group.
EP 0,818,442 illustrates MMP inhibitors of formula C: 
wherein Ar is optionally substituted phenyl or naphthyl, Z can be absent and X and Y can be a variety of substituents. Compounds of this sort are not considered to be part of the present invention.
The compounds of the present invention act as inhibitors of MPs, in particular TACE, MMPs, and/or aggrecanase. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibition of aggrecanase, TACE, and other metalloproteases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of OA and RA.
Accordingly, one object of the present invention is to provide novel spiro-cyclic hydroxamic acids useful as MMP, TACE, and/or aggrecanase inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders, comprising: administering to a host, in need of such treatment, a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method of treating a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method comprising: administering a compound of the present invention or a pharmaceutically acceptable salt or prodrug form thereof in an amount effective to treat a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof.
It is another object of the present invention to provide novel compounds of the present invention for use in therapy.
It is another object of the present invention to provide the use of novel compounds of the present invention for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPS, TACE, aggrecanase, or a combination thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, C, R1, R2, R2a, R2b, R3, Z, Ua, Xa, Ya, and Za are defined below, are effective metalloprotease inhibitors.
[1] Thus, in an embodiment, the present invention provides a novel compound of formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94COR5, xe2x80x94CO2H, CH2CO2H, xe2x80x94CO2R6, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)COR5, xe2x80x94N(OH)CHO, xe2x80x94SH, xe2x80x94CH2SH, xe2x80x94S(O)(xe2x95x90NH)Ra, xe2x80x94SN2H2Ra, xe2x80x94PO(OH)2, and xe2x80x94PO(OH)NHRa;
ring B is a 3-13 membered non-aromatic carbocycle or heterocycle comprising: carbon atoms, 0-3 carbonyl groups, 0-4 double bonds, and from 0-2 ring heteroatoms selected from O, N, NR2, and S(O)p, provided that ring B contains other than a Sxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94O bond;
ring C forms a spiro ring on Ring B and is a 3-13 membered carbocycle or heterocycle comprising: carbon atoms, 0-3 carbonyl groups, 0-4 double bonds, and from 0-5 ring heteroatoms selected from O, N, NR2, and S(O)p and substituted with 0-6 Re, provided that ring C contains other than a Sxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94O bond;
Z is absent or selected from a C3-13 carbocycle substituted with 0-5 Rb and a 5-14 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)O, OC(O), C(O)NRa1, NRa1C(O), OC(O)O, OC(O)NRa1, NRa1C(O)O, NRa1C(O)NRa1, S(O)p, S(O)pNRa1, NRa1S(O)p, and NRa1SO2NRa1;
Xa is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Ya is absent or selected from O, NRa1, S(O)p, and C(O);
Za is selected from H, a C3-13 carbocycle substituted with 0-5 Rc and a 5-14 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1 is selected from H, C1-4 alkyl, phenyl, and benzyl;
R2 is selected from Q, Cl, F, (C1-10 alkylene substituted with 0-3 Rb1)xe2x80x94Q, (C2-10 alkenylene substituted with 0-3 Rb1)xe2x80x94Q, (C2-10 alkynylene substituted with 0-3 Rb1)xe2x80x94Q, (CRaRa1)r1O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)Oxe2x80x94C2-5 alkenylene, (CRaRa1)r1C(O)Oxe2x80x94C2-5 alkynylene, (CRaRa1)r1OC(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)NRaRa1, (CRaRa1)r1C(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaC(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1OC(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1OC(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaC(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaC(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1S(O)p(CRaRa1)rxe2x80x94Q, (CRaRa1)r1SO2NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRaSO2(CRaRa1)rxe2x80x94Q, and (CRaRa1)r1NRaSO2NRa(CRaRa1)rxe2x80x94Q;
R2a is selected from H, C1-6 alkyl, ORa, NRaRa1, and S(O)pRa;
R2b is H or C1-6 alkyl;
Q is selected from H, a C3-13 carbocycle substituted with 0-5 Rd and a 5-14 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rd;
R3 is selected from Q1, Cl, F, C1-6 alkylene-Q1, C2-6 alkenylene-Q1, C2-6 alkynylene-Q1, (CRaRa1)r1O(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1NRaC(O)(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1C(O)NRa(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1C(O)(CRaRa1)rxe2x80x94Q1, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q1, (CRaRa12)r1S(O)p(CRaRa1)rxe2x80x94Q1, and (CRaRa1)r1SO2NRa(CRaRa1)rxe2x80x94Q1;
Q1 is selected from H, phenyl substituted with 0-3 Rd, naphthyl substituted with 0-3 Rd and a 5-10 membered heteroaryl comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached to form a 5 or 6 membered ring comprising carbon atoms and from 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, and CF2CF3;
Rb1, at each occurrence, is independently selected from ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, and NRaRa1;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, C3-10 carbocycle substituted with 0-3 Rc1 and a 5-14 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rc1;
alternatively, when two Rc groups are attached to the same carbon atom, they form a spiro ring D that is a 3-11 membered carbocycle substituted with 0-2 Rc1 or a 3-13 membered heterocycle comprising: carbon atoms and from 1-4 ring heteroatoms selected from O, N, and S(O)p and substituted with 0-2 Rc1, provided that ring D contains other than a Sxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94O bond;
alternatively, when two Rc groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-7 membered saturated, partially saturated or unsaturated ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p; this ring is substituted with 0-2 Rc1;
Rc1, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, CH2F, and CHF2;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, C3-10 carbocycle and a 5-14 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
Re, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, C3-10 carbocycle substituted with 0-2 Rc1, (CRaRa1)r1xe2x80x94C3-10 carbocycle substituted with 0-2 Rc1, a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1, and (CRaRa1)r1xe2x80x945-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1;
R5, at each occurrence, is selected from C1-10 alkyl substituted with 0-2 Rb, and C1-8 alkyl substituted with 0-2 Rf;
Rf, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-8 alkyl substituted with 1-2 Rg, C3-8 cycloalkyl substituted with 1-2 Rg, and phenyl substituted with 0-2 Rb;
Rg, at each occurrence, is selected from C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[2] In a preferred embodiment, the present invention provides a novel compound of formula II: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)COR5, xe2x80x94N(OH)CHO, xe2x80x94SH, and xe2x80x94CH2SH;
ring B is a 4-7 membered non-aromatic carbocyclic or heterocyclic ring comprising: carbon atoms, 0-1 carbonyl groups, 0-1 double bonds, and from 0-2 ring heteroatoms selected from O, N, and NR2, provided that ring B contains other than a Oxe2x80x94O bond;
ring C forms a spiro ring on Ring B and is a 4-10 membered carbocycle substituted with 0-3 Re or a 4-10 membered heterocycle comprising: carbon atoms, 0-3 carbonyl groups, 0-4 double bonds, and from 0-4 ring heteroatoms selected from O, N, NR2, and S(O)p and substituted with 0-3 Re, provided that ring C contains other than a Sxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94O bond;
Z is absent or selected from a C3-11 carbocycle substituted with 0-4 Rb and a 5-11 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)O, C(O)NRa1, NRa1C(O), S(O)p, and S(O)pNRa1;
Xa is absent or selected from C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene;
Ya is absent or selected from O and NRa1;
Za is selected from H, a C3-10 carbocycle substituted with 0-5 Rc and a 5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1 is selected from H, C1-4 alkyl, phenyl, and benzyl;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRaRa1)r1O(CRaRa1)rxe2x80x94Q, (CRaRa1)r1NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q, (CRaRa1)rC(O)NRaRa1, (CRaRa1)r1C(O)NRa(CRaRa1)rxe2x80x94Q, (CRaRa1)r1S(O)p(CRaRa1)rxe2x80x94Q, and (CRaRa1)r1SO2NRa(CRaRa1)rxe2x80x94Q;
Q is selected from H, a C3-6 carbocycle substituted with 0-5 Rd, and a 5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-5 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
alternatively, Ra and Ra1 when attached to a nitrogen are taken together with the nitrogen to which they are attached to form a 5 or 6 membered ring comprising carbon atoms and from 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl and benzyl;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, C3-6 carbocycle substituted with 0-2 Rc1 and a 5-6 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1;
alternatively, when two Rc groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-6 membered saturated, partially saturated or unsaturated ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p;
Rc1, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, CH2F, and CHF2;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, xe2x80x94CN, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, C3-6 carbocycle and a 5-6 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
Re, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, C3-10 carbocycle substituted with 0-2 Rc1, (CRaRa1)r1xe2x80x94C3-10 carbocycle substituted with 0-2 Rc1, a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1, and (CRaRa1)r1-5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1;
R5, at each occurrence, is selected from C1-6 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Rf;
Rf, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, and xe2x80x94CH(R8)OC(xe2x95x90O)OR9;
R7 is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-6 alkyl substituted with 1-2 Rg, C3-6 cycloalkyl substituted with 1-2 Rg, and phenyl substituted with 0-2 Rb;
Rg, at each occurrence, is selected from C1-4 alkyl, C3-6 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[3] In another preferred embodiment, the present invention provides a novel compound of formula IIIa or IIIb: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94N(OH)CHO, and xe2x80x94N(OH)COR5;
Z is absent or selected from a C5-6 carbocycle substituted with 0-3 Rb and a 5-6 membered heteroaryl comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rb;
Ua is absent or is selected from: O, NRa1, C(O), C(O)NRa1, S(O)p, and S(O)pNRa1;
Xa is absent or selected from C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene
Ya is absent or selected from O and NRa1;
Za is selected from H, a C5-10 carbocycle substituted with 0-3 Rc and a 5-10 membered heterocycle comprising carbon atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, Oxe2x80x94O, S(O)pxe2x80x94O, Oxe2x80x94S(O)p or S(O)pxe2x80x94S(O)p group;
R1 is selected from H, C1-4 alkyl, phenyl, and benzyl;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRaRa1)r1C(O)(CRaRa1)rxe2x80x94Q, (CRaRa1)r1C(O)O(CRaRa1)rxe2x80x94Q, (CRaRa2)r1C(O)NRaRa1, (CRaRa2)r1C(O)NRa(CRaRa1)rxe2x80x94Q, and (CRaRa1)r1S(O)p(CRaRa1)rxe2x80x94Q;
Q is selected from H, a C3-6 carbocycle substituted with 0-3 Rd and a 5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl, and benzyl;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, cyclopropyl, 1-methylcyclopropyl, and cyclobutyl;
alternatively, when two Rc groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-6 membered saturated ring consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, and phenyl;
Re, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, C3-10 carbocycle substituted with 0-2 Rc1, (CRaRa1)r1xe2x80x94C3-10 carbocycle substituted with 0-2 Rc1, a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1, and (CRaRa1)r1-5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1;
R5, at each occurrence, is selected from C1-4 alkyl substituted with 0-2 Rb, and C1-4 alkyl substituted with 0-2 Rf;
Rf, at each occurrence, is selected from phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4;
r1, at each occurrence, is selected from 0, 1, 2, 3, and 4;
s and s1 combine to total 2, 3, or 4; and
s2 and s3 combine to total 2, 3, 4, or 5.
[4] In another preferred embodiment, the present invention provides a novel compound of formula IVa or IVb: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
Z is absent or selected from phenyl substituted with 0-3 Rb, pyridyl substituted with 0-3 Rb, thiazolyl substituted with 0-3 Rb, thienyl substituted with 0-3 Rb, and isoxazolyl substituted with 0-3 Rb;
Ua is absent or is O;
Xa is absent or is CH2 or CH2CH2;
Ya is absent or is O;
Za is selected from H, phenyl substituted with 0-3 Rc, and a 5-10 membered heterocycle substituted with 0-3 Rc and selected from the group: pyridyl, quinolinyl, imidazolyl, benzimidazolyl, indolyl, 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl, 1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl, 3,4-dihydro-2H-chromen-4-yl, 2H-chromen-4-yl, and pyrazolyl;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, or Oxe2x80x94O group;
R1 is selected from H, CH3, and CH2CH3;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkynylene-Q, C(O)(CRaRa1)rxe2x80x94Q, C(O)O(CRaRa1)rxe2x80x94Q, C(O)NRa(CRaRa1)rxe2x80x94Q, and S(O)p(CRaRa1)rxe2x80x94Q;
Q is selected from H, cyclopropyl substituted with 0-1 Rd, cyclobutyl substituted with 0-1 Rd, cyclopentyl substituted with 0-1 Rd, cyclohexyl substituted with 0-1 Rd, phenyl substituted with 0-2 Rd and a heteroaryl substituted with 0-3 Rd, wherein the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl;
Ra, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra1, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra2, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2 and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, cyclopropyl, 1-methylcyclopropyl, and cyclobutyl;
alternatively, when two Rc groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-6 membered saturated ring consisting of: carbon atoms and 0-1 heteroatoms selected from the group consisting of N, O, and S(O)p;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3 and phenyl;
Re, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, C3-10 carbocycle substituted with 0-2 Rc1, (CRaRa1)r1xe2x80x94C3-10 carbocycle substituted with 0-2 Rc1, a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1, and (CRaRa1)r1-5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3;
r1, at each occurrence, is selected from 0, 1, 2, and 3;
s and s1 combine to total 2, 3, or 4; and
s2 and s3 combine to total 2, 3, 4, or 5.
[5] In another preferred embodiment, the present invention provides a novel compound of formula IVa or IVb, wherein;
Z is absent or selected from phenyl substituted with 0-3 Rb and pyridyl substituted with 0-3 Rb;
Ua is absent or is O;
Xa is absent or is CH2 or CH2CH2;
Ya is absent or is O;
Za is selected from H, phenyl substituted with 0-3 Rc, pyridyl substituted with 0-3 Rc, and quinolinyl substituted with 0-3 Rc;
provided that Z, Ua, Ya, and Za do not combine to form a Nxe2x80x94N, Nxe2x80x94O, Oxe2x80x94N, or Oxe2x80x94O group;
R1 is selected from H, CH3, and CH2CH3;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkynylene-Q, C(O)(CRaRa1)rxe2x80x94Q, C(O)O(CRaRa1)rxe2x80x94Q, C(O)NRa(CRaRa1)rxe2x80x94Q, and S(O)p(CRaRa1)rxe2x80x94Q;
Q is selected from H, cyclopropyl substituted with 0-1 Rd, cyclobutyl substituted with 0-1 Rd, cyclopentyl substituted with 0-1 Rd, cyclohexyl substituted with 0-1 Rd, phenyl substituted with 0-2 Rd and a heteroaryl substituted with 0-3 Rd, wherein the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl;
Ra, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra1, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra2, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Rb, at each occurrence, is independently selected from C1-4 alkyl, ORa, Cl, F, xe2x95x90O, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, and CF3;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3 and phenyl;
Re, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, CF2CF3, C3-10 carbocycle substituted with 0-2 Rc1, (CRaRa1)r1xe2x80x94C3-10 carbocycle substituted with 0-2 Rc1, a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1, and (CRaRa1)r1-5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-2 Rc1;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, and 3;
r1, at each occurrence, is selected from 0, 1, 2, and 3;
s and s1 combine to total 2, 3, or 4; and
s2 and s3 combine to total 2, 3, 4, or 5.
[6] In another preferred embodiment, the present invention provides a novel compound of formula IVa or IVb, wherein;
Z is phenyl, thiazolyl, thienyl or isoxazolyl;
Ua is absent or is O;
Xa is absent or is CH2 or CH2CH2;
Ya is absent or is O;
Za is a 5-10 membered heterocycle substituted with 0-2 Rc and selected from the group: 4-pyridyl, 4-quinolinyl, 1H-benzimidazol-1-yl, 1H-indol-1-yl, and 1H-indol-3-yl, 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl;
R1 is H;
Rc, at each occurrence, is independently selected from methyl, ethyl, propyl, isopropyl, butyl, t-butyl, CF3, CHF2, CH2F, CF2CH3, C(CH3)2F, NH2, NH(CH3), N(CH3)2, cyclopropyl, 1-methylcyclopropyl, and cyclobutyl;
s and s1 combine to total 2, 3, or 4; and
s2 and s3 combine to total 2, 3, 4, or 5.
[7] In another preferred embodiment, the present invention provides a compound selected from the group:
(7S,8R)-N-hydroxy-8-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1,4-dioxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-oxaspiro[4.4]nonane-7-carboxamide;
(5S,7S,8R)-N-hydroxy-8-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1-oxaspiro[4.4]nonane-7-carboxamide;
(2S,3R)-N-hydroxy-3-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-6,10-dioxaspiro[4.5]decane-2-carboxamide;
(7S,8R)-N-hydroxy-8-({4-[(2-methyl-4-quinolinyl)methoxy]benzoyl}amino)-1,4-dithiaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-{[4-(2-butynyloxy)benzoyl]amino}-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-({4-[(2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(2-tert-butyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-({4-[(2-methyl-1H-indol-3-yl)methyl]benzoyl}amino)-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-[(4-{[2-(difluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(2-cyclopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(2-cyclobutyl-1-H-benzimidazol-1-yl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-({4-[(2-isopropyl-1H-imidazol-1-yl)methyl]benzoyl}amino)-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-({4-[(2-methyl-1H-indol-1-yl)methyl]benzoyl}amino)-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-[(4-{[2-(1-methylcyclopropyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-[(4-{[2-(fluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-[(4-{[2-(1-fluoro-1-methylethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-{[4-(1H-indol-3-ylmethyl)benzoyl]amino}-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-[(4-{[2-(1,1-difluoroethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(2,3-dimethyl-1H-indol-1-yl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(2-ethyl-1H-indol-3-yl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-[(4-{[2-(trifluoromethyl)-1H-indol-1-yl]methyl}benzoyl)amino]-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-{[4-(1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl)benzoyl]amino}-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-{[4-(3,4-dihydro-2H-chromen-4-yl)benzoyl]amino}-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-{[4-(2H-chromen-4-yl)benzoyl]amino}-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
N-{(5R,7R,8S)-8-[(hydroxyamino)carbonyl]-1-oxaspiro[4.4]non-7-yl}-2-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]-1,3-thiazole-4-carboxamide;
(5R,7S,8R)-8-({4-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-({4-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]benzoyl}amino)-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-[(4-{[2-(trifluoromethyl)-4-quinolinyl]methyl}benzoyl)amino]-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(2-ethyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-({4-[(2-isopropyl-4-quinolinyl)methyl]benzoyl}amino)-1-oxaspiro[4.4]nonane-7-carboxamide
(5R,7S,8R)-8-[(4-{[2-(dimethylamino)-4-quinolinyl]methyl}benzoyl)amino]-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(2-cyclopropyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-{[4-(1,3-dihydrofuro[3,4-b]quinolin-9-ylmethyl)benzoyl]amino}-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(2,3-dimethyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-N-hydroxy-8-[(4-{[2-methyl-8-(trifluoromethyl)-4-quinolinyl]methyl}benzoyl)amino]-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(3-ethyl-2-methyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(2,6-dimethyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(6-chloro-2-methyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(6-fluoro-2-methyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide;
(5R,7S,8R)-8-({4-[(7-chloro-2-methyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide; and
(5R,7S,8R)-8-({4-[(2,6-dimethyl-4-pyridinyl)methyl]benzoyl}amino)-N-hydroxy-1-oxaspiro[4.4]nonane-7-carboxamide; or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating or preventing an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof.
In another embodiment, the present invention provides a novel method of treating a disease or condition, wherein the disease or condition is referred to as acute infection, acute phase response, age related macular degeneration, alcoholism, allergy, allergic asthma, anorexia, aneurism, aortic aneurism, asthma, atherosclerosis, atopic dermatitis, autoimmune disease, autoimmune hepatitis, Bechet""s disease, cachexia, calcium pyrophosphate dihydrate deposition disease, cardiovascular effects, chronic fatigue syndrome, chronic obstruction pulmonary disease, coagulation, congestive heart failure, corneal ulceration, Crohn""s disease, enteropathic arthropathy, Felty""s syndrome, fever, fibromyalgia syndrome, fibrotic disease, gingivitis, glucocorticoid withdrawal syndrome, gout, graft versus host disease, hemorrhage, HIV infection, hyperoxic alveolar injury, infectious arthritis, inflammation, intermittent hydrarthrosis, Lyme disease, meningitis, multiple sclerosis, myasthenia gravis, mycobacterial infection, neovascular glaucoma, osteoarthritis, pelvic inflammatory disease, periodontitis, polymyositis/dermatomyositis, post-ischaemic reperfusion injury, post-radiation asthenia, psoriasis, psoriatic arthritis, pulmonary emphysema, pydoderma gangrenosum, relapsing polychondritis, Reiter""s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sepsis syndrome, Still""s disease, shock, Sjogren""s syndrome, skin inflammatory diseases, solid tumor growth and tumor invasion by secondary metastases, spondylitis, stroke, systemic lupus erythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener""s granulomatosis.
In another embodiment, the present invention provides novel compounds of the present invention for use in therapy.
In another embodiment, the present invention provides the use of novel compounds of the present invention for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof.
This invention also encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional even more preferred embodiments of the present invention. It is also understood that each and every element of any embodiment is intended to be a separate specific embodiment. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Geometric isomers of double bonds such as olefins and Cxe2x95x90N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
Preferably, the molecular weight of compounds of the present invention is less than about 500, 550, 600, 650, 700, 750, 800, 850, or 900 grams per mole. More preferably, the molecular weight is less than about 850 grams per mole. Even more preferably, the molecular weight is less than about 750 grams per mole. Still more preferably, the molecular weight is less than about 700 grams per mole.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
The term xe2x80x9cindependently selected fromxe2x80x9d, xe2x80x9cindependently, at each occurrencexe2x80x9d or similar language, means that the labeled R substitution group may appear more than once and that each appearance may be a different atom or molecule found in the definition of that labeled R substitution group. Thus if the labeled Ra substitution group appear four times in a given permutation of Formula I, then each of those labeled Ra substitution groups may be a different group falling in the definition of Ra. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw, where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic groupxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl, 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl, 1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl, and 3,4-dihydro-2H-chromen-4-yl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
As used herein, xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit a desired metalloprotease in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55, occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased increased anti-inflammatory effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A variety of compounds of formula (I) wherein A is hydroxamic acid group are prepared from the corresponding esters via several routes known in the literature (Scheme 1). The methyl ester of 1 (R11=Me) is directly converted to hydroxamic acid 2 by treatment with hydroxylamine under basic conditions such as KOH or NaOMe in solvents such as methanol. The methyl ester of 1 (R11=Me) can also be converted to O-benzyl protected hydroxamic acid with O-benzylhydroxylamine under similar conditions or using Weinreb""s trimethylaluminum conditions (Levin, J. I.; Turos, E.; Weinreb, S. M. Syn. Commun. 1982, 12, 989) or Roskamp""s bis[bis(trimethylsilyl)amido]tin reagent (Wang, W.-B.; Roskamp, E. J. J. Org. Chem. 1992, 57, 6101). The benzyl ether is removed by methods well known in the literature such as hydrogenation using palladium on barium sulfate in hydrogen, to give compound 2. Alternatively, 2 can be prepared through the carboxylic intermediate 3. Carboxylic acid 3 is converted to 2 via coupling with hydroxylamine, or O-benzylhydroxylamine followed by deprotection. 
The xcex2-amino acid moiety in formula (I) can be synthesized following a variety of literature routes as reviewed in xe2x80x9cEnantioselective Synthesis of xcex2-Amino Acidsxe2x80x9d (E. Juaristi, Ed. Wiley-VCH, 1997). One representative approach using Davies protocol is summarized in Scheme 2 (J. Chem. Soc. Perkin Trans I, 1994, 1411). Michael addition of lithium amide 5 to 4 gives cis product 6. The stereochemical configuration of 6 is governed by the chirality of 5. De-benzylation of 6 provides cis-xcex2-amino acid 7. The trans-xcex2-amino acid 9 can be prepared by epimerization of 6 followed by de-benzylation. Since both amine enantiomers of 5 are commercially available, this approach provides ready access to both cis and trans isomers (7 and 9), as well as their antipodes. 
Alternatively, these xcex2-amino acids can be prepared from the corresponding dicarboxylate derivatives (Scheme 3). The dicarboxylate derivatives can be de-symmetrized through enzymatic resolution (for an example with lipase, see Gais, H.-J. et al, J. Am. Chem. Soc. 1989, 54, 5115), or through chemical resolution (for an example with TADOLates, see Seebach, D. et al. Angew. Chem. Int. Ed. Engl. 1995, 34, 2395). The optically pure mono-ester 11 is converted to Cbz protected xcex2-amino acid ester 12 through Curtius rearrangement (for a related example, see Kobayashi, S. et al. Tetrahedron Lett. 1984, 25, 2557). Removal of Cbz protecting group provides cis-amino acid ester 13. The corresponding trans analogue of 13 can be prepared from the ester of trans di-carboxylic acid of 10 following same sequence. 
A series of compounds of formula (I) wherein ring B is a cyclopentane and ring C is a dioxolane are prepared following the sequence outlined in Scheme 4. The acid of compound 14 can be protected as the benzyl ester and the cyclohexene 15 is oxidized to the bis-acid and cyclized to the ketone 17 (for a related example see: Gais et al. J. Org. Chem. 1989, 54, 5115). The ketone is converted to the ethylene ketal 18. Protecting group manipulations and Curtius rearrangement (for a related example, see Kobayashi, S. et al, Tetrahedron Lett. 1984, 25, 2557) give intermediate 20. Hydrogenolysis gives amino acid ester 21. 21 is coupled with acid 22 to provide 23. Which is converted to the hydroxamic acid 24. 
A series of compounds of formula (I) wherein ring B is cyclopentane and ring C is a dioxane, dioxepane, dithialane, dithiane, or dithiepane are prepared following the sequence outlined in Scheme 5. The ethylene ketal 23 deketalized with HCl and the resultant ketone reketalized with the appropriate diol or thiol to give 25 and 26 respectively, which can be converted as previously described to the desired hydroxamic acid. 
A series of compounds of formula (I) wherein ring B is cyclopentane and ring C is a tetrahydrofuran are prepared following the sequence outlined in Scheme 6. Ketone 17 is treated with allyltrimethylsilane in the presence of titanium tetrachloride to give 28, hydroboration/oxidation yields the primary alcohol which is cyclized to the the tetrahydrofuran 30. Conversion of 30 to the desired amine 33 and then amide and finally hydroxamic acid 34 proceeds through the steps as previously described. 
A series of compounds of formula (I) wherein ring B is cyclopentane and ring C is a tetrahydropyran are prepared following the sequence outlined in Scheme 7. Alcohol 29 is oxidized and converted to the olefin using methylene trphenylphosphorane followed by a hydroboration/oxidation sequence to deliver diol 35. Cyclization followed by a similar sequece as described earlier delivers 40. 
A series of compounds of formula (I) wherein ring B is cyclopentane and ring C is an oxetane are prepared following the sequence outlined in Scheme 8. Olefin 28 is ozonized and reduced the diol 41. Conversion to the primary bromide followed by cycliztion (NaH, DMF) delivers the oxetane 43. Following a similar sequence as described earlier delivers 47. 
A series of compounds of formula (I) wherein ring B is a cyclopentane and ring C is an azetidine, pyrrolidine or a piperidine are prepared following the sequence outlined in Scheme 9. The benzylimine of ketone 17 is treated with Grignard reagent 58 (for a related example see: Berthe et. al. Tetrahedron Letters, 1997, 38, 1393-1396). The olefin 49 is then oxidized to the aldehyde 50. For azetidine formation (n=1) aldehyde 50 is reduced to the alcohol and cyclized using Mitsunobu conditions (for azetidine formation of benzyl amines using Mitsunobu conditions, see: Sammes and Smith, J. Chem. Soc. Chem Commun. 1983, 682). For pyrrolidine and piperidine formation (n=5,6), the aldehyde is converted to the desired ring by hydrogenolysis (for formation of 5 or 6-membered rings by reductive amination, see: Lubell, et al: J. Org. Chem. 1996, 61, 9447 and Watanabe, et al: J. Org. Chem, 1989, 54, 4088). Appropriate protection of the nitrogen is followed by conversion of the acid to a protected amine through a Curtius rearrangement to give 53. Protecting group manipulation and coupling to 22 yields 55. The BOC protecting group can be removed (TFA) and the nitrogen functionalized by amidation, alkylation, reductive amination, sulfonylation, etc. Conversion to the hydroxamate 57 proceeds as previously described. 
A series of compounds of formula (I) wherein A is N-formylhydroxylamino group are prepared following the sequence outlined in Scheme 10. Starting from trans-hydroxy ester 58, Wenreib or Roskamp amide formation with O-t-butylhydroxylamine gives 59 (Levin, J. I.; Turos, E.; Weinreb, S. M. Syn. Commun. 1982, 12, 989 and Wang, W.-B.; Roskamp, E. J. J. Org. Chem. 1992, 57, 6101). xcex2-Lactam is formed under Mitsunobu conditions (Mitsunobu, O. Synthesis, 1981, 1). Opening of lactam 60 with methylamine followed by N-formylation provide 62. The N-methyl amide moiety of 62 is converted to carboxylic acid by nitrosation with N2O4 or NaNO2, and hydrolysis with LiOOH (Evans, D. A.; Carter, P. H.; Dinsmore, C. J.; Barrow, J. C.; Katz, J. L.; Kung, D. W. Tetrahedron Lett. 1997, 38, 4535). Acid 63 is converted to 66 as described previously. Acid hydrolysis of t-Butyl group in 66 completes the synthesis. 
A series of compounds of formula (I) wherein A is mercaptomethyl group are prepared following the sequence outlined in Scheme 11. Saponification and hydroboration of 68 give alcohol 70. Mitsunobu reaction with thioacetic acid followed by lithium hydroxide hydrolysis provides the desired thiol 72. 
A variety of compounds of formula (I) wherein Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Za is a functionalized phenyl group can be prepared by methods described in Scheme 12. Intermediate 73, available from schemes described previously, is converted to phenol 74 by hydrogenolysis. Phenol 74 is used as common intermediates for structure diversification. Reaction of 74 with R10xe2x80x94X provides 75, an alternative is the reaction of 74 with R10xe2x80x94OH under Mitsunobu conditions to produce 75. R10 can be appended directly to the aromatic ring by converting 74 to an aryl triflate then reaction with an organometallic in the presence of a palladium (0) catalyst to give 76. 74 can also be reacted with acyl halides or isocyanates to afford 79. Biaryl ethers 78 can be produced by treatment of 74 with aryl boronic acids in the presence of a copper catalyst. Esters 74-76 and 78-79 are converted to the hydroxamic acids following the sequences outlined in Scheme 1. 
Another procedure for the synthesis of cyclic xcex2-amino acids useful for the preparation of compounds of formula I uses the well documented [2+2] cycloaddition of chlorosulfonylisocyanate with olefins (Scheme 13, Dhar, D. N.; Murthy, K. S. K. Synthesis 1986, 437-449). When 80 is reacted with chlorosulfonylisocyanate the resulting xcex2-lactam intermediate 81 can be opened to afford cyclic xcex2-amino acids using a variety of conditions, but most conveniently with chlorotrimethylsilane/methanol. The methyl ester 13 can then be converted to compounds of formula I followed our usual procedure of attaching carboxcylic acid 20 to provide 82 then hydroxamic acid 83 is formed by our standard conditions. The trans xcex2-amino acids 84 are available by equilibration of cis amide ester 82 under basic conditions. 
An alternative synthesis of 83 begins with formation of benzyl hydroxamate 86 from trans xcex2-hydroxy carboxylate 85 (Scheme 14). Intramolecular cyclization of 86 under Mitsunobu conditions (Bellettini, J. R.; Miller, M. J. Tetrahedron Letters 1997, 38, 167-168) then affords benzyl protected hydroxy xcex2-lactam 87. Removal of the benzyl group by hydrogenolysis and reduction of the intermediate N-hydroxy xcex2-lactam provides 81, which can be converted to final products as shown in the previous scheme. 
Outlined in Scheme 15 are compounds of Formula I wherein ring B is a cyclohexane. The regioisomeric ketones 88 and 89 are available from 15 via Wacker oxidation. The alcohols 90 and 91 are then available from previously described methods. 
Alcohols 90 (Scheme 16) and 91 (Scheme 17) can then be converted to 4-, 5-, and 6-membered spirocyclic ethers following chemistry that was outlined in the previously noted schemes. 
One diastereomer of a compound of Formula I may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention. 
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al. Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al. Tetrahedron Lett. 1995, 36, 8937-8940.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.